ProjectAbstract The interstitial lung diseases (ILDs) are a family of closely related lung conditions characterized by alveolar inflammation, injury, and/or fibrosis not due to infection or neoplasia. Idiopathic pulmonary fibrosis (IPF), a fibroticILDaffectsnearly1in200olderadultsandcarriesapoorprognosis.Therapeuticoptionsarelimited, andtodatenostudyhastestedinterventionsthatpreventthedevelopmentofafibroticILD.Weareconducting studiesthatarepreparatorytoandrequisiteforfutureclinicaltrialsofpreventativeIPFandILDinterventions. To move toward this goal, in the previous award period, we established the construct validity of a novel quantitative computed tomographic (CT)-based measure, termed high attenuation areas (HAAs), as an imaging biomarker of early, mild alveolar inflammation, injury, and fibrosis in a large cohort of community dwelling adults enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA), an ongoing NHLBI-funded prospective cohort study of 6,814 adults age 45 and older at enrollment in 2000 through 2002. These data strongly support HAA as a novel and relevant quantitative biomarker of the earliest biological changes in the lungparenchymathatlaterleadtoILD,yetadditionalworkisrequiredtomovethesefindingsintofutureclinical trialsandintotheclinic.Inthecurrentapplication,weproposetoexaminethepulmonaryhistopathologyand biologyofHAAinfirst-degreerelativesofadultswithclinicallydiagnosedILD.Toachievethesegoals,wewill initiate the Families At-Risk for ILD (FAR-ILD) study, a prospective study of adults with ILD and their first- degreerelativesdesignedtoidentifyadultswithsubclinicalILDandthoseat-riskforincidentILD.Wewillalso usetheMESAcohorttodevelopaclinicalpredictionmodelforincidentradiologicILD.Ourstudywillprovide strong evidence that will inform future studies of preventative interventions for adults at high risk of ILD. Our results will also help identify potential targetable pathways for prevention in at-risk adults and inform future phase2trialofapreventativeintervention,suchaspirfenidone,nintedanib,orN-acetylcysteine(whichmaybe effective in subsets of individuals), or perhaps by targeting a pathway identified through our study of the biologyofearlysubclinicalILD.